We defined injury-induced transcriptome states in 4502 kidney transplant biopsies taken 1 day to 45 years post-transplant using genome-wide microarrays. Injury was measured by injury-induced gene sets and classifiers previously developed in transplants. In principal component analysis, PC1 correlated with both acute and chronic kidney injury and related inflammation, and PC2 with time post-transplant. PC3 was a novel dimension that correlated with epithelial remodeling pathways. Both PC1 and PC3 correlated with reduced survival, PC1 effects strongly increasing with time whereas PC3 effects being time-independent. In this model, we studied the expression of genes annotated in native kidneys in epithelial cells with failed repair: 12 "New" gene sets previously defined in single nucleus RNA sequencing of native kidneys with AKI (Genome Med.14(1):103). The "New4" gene sets reflecting epithelial-mesenchymal transition (EMT) correlated with injury PC1, lower eGFR, higher donor age, and future failure as strongly as any gene sets previously derived in transplants, independent of nephron segment of origin and graft rejection. These results suggest that there are two distinct dimensions in kidney transplant response to injury: PC1, AKI-induced changes, failed repair, and inflammation; and PC3, a response involving epithelial remodeling without inflammation. Increasing kidney age amplifies PC1 and particularly PC3.

• Klíčová slova
• Molecular diagnosis, Nephrology, Organ transplantation, Transplantation,
• Publikační typ
• časopisecké články MeSH

Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. To examine this question, we studied genome-wide microarray results from 5086 kidney transplant biopsies (from 4170 patients). An updated molecular archetypal analysis designated 56% of biopsies as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower estimated glomerular filtration rate, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR, respectively, diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems.

• Klíčová slova
• ABMR, TCMR, biopsy, gene expression, gradients, kidney transplant, microarray, transplant rejection,
• MeSH
• biopsie MeSH
• dospělí MeSH
• hodnoty glomerulární filtrace MeSH
• isoprotilátky imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• přežívání štěpu imunologie   MeSH
• prognóza MeSH
• rejekce štěpu * patologie   imunologie   etiologie   MeSH
• rizikové faktory MeSH
• T-lymfocyty imunologie   MeSH
• transplantace ledvin * škodlivé účinky   MeSH
• vyšetření funkce ledvin MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• isoprotilátky MeSH

UNLABELLED: Although prolonged-release tacrolimus (PR-T) is widely approved for posttransplantation immunosuppression in kidney recipients, large-scale studies are required to assess long-term outcomes. We present follow-up data from the Advagraf-based Immunosuppression Regimen Examining New Onset Diabetes Mellitus in Kidney Transplant Recipients (ADVANCE) trial, in which kidney transplant patients (KTPs) received corticosteroid minimization with PR-T. METHODS: ADVANCE was a 24-wk, randomized, open-label, phase-4 study. De novo KTPs received PR-T with basiliximab and mycophenolate mofetil and were randomized to receive an intraoperative corticosteroid bolus plus tapered corticosteroids until day 10 (arm 1) or an intraoperative corticosteroid bolus (arm 2). In this 5-y, noninterventional follow-up, patients received maintenance immunosuppression according to standard practice. The primary endpoint was graft survival (Kaplan-Meier). Secondary endpoints included patient survival, biopsy-confirmed acute rejection-free survival, and estimated glomerular filtration rate (4-variable modification of diet in renal disease). RESULTS: Follow-up study included 1125 patients. Overall graft survival at 1 and 5 y posttransplantation was 93.8% and 88.1%, respectively, and was similar between treatment arms. At 1 and 5 y, patient survival was 97.8% and 94.4%, respectively. Five-year graft and patient survival rates in KTPs who remained on PR-T were 91.5% and 98.2%, respectively. Cox proportional hazards analysis demonstrated similar risk of graft loss and death between treatment arms. Five-year biopsy-confirmed acute rejection-free survival was 84.1%. Mean ± standard deviation values of estimated glomerular filtration rate were 52.7 ± 19.5 and 51.1 ± 22.4 mL/min/1.73 m2 at 1 and 5 y, respectively. Fifty adverse drug reactions were recorded, probably tacrolimus-related in 12 patients (1.5%). CONCLUSIONS: Graft survival and patient survival (overall and for KTPs who remained on PR-T) were numerically high and similar between treatment arms at 5 y posttransplantation.

• Publikační typ
• časopisecké články MeSH

Despite an increasing quality of life after renal transplantation, the number of recipients undertaking paid professional work remains relatively low. Employment after kidney transplantation became a new important marker of clinically significant health recovery. Furthermore, for social and economic reasons, returning to work and participation in social life may be considered as an objective parameter that demonstrate the effectiveness of transplantation. The objectives of the following study were to evaluate the factors that determine resuming paid work after renal transplantation, to assess a patient's decision about returning to professional activity by comparative analysis of renal transplant recipients from Poland, Czech Republic and Germany, and to identify groups of patients exposed to professional exclusion in those EU countries. Five hundred renal transplant recipients from three EU countries were included into the study. The two main research methods used in the study were the SF-36 questionnaire, constructed and validated to assess the quality of life after kidney transplantation and a questionnaire constructed for the purposes of this study. Multifactorial analysis identified several risk factors associated with professional exclusions after kidney transplantation, namely young or advanced age, female gender, lack of education, place of residence in rural areas, long period of illness, and lack of occupational activity before transplantation. Despite the high standards of social care and rehabilitation support, patients in Germany failed to take up professional activity after kidney transplantation in more cases than those in Poland and Czech Republic. Surprisingly, the objective function of the kidney (creatinine level) and the multidimensional assessment of quality of life (SF-36 survey) did not have a significant association with the employment status after renal transplantation.

• Klíčová slova
• employment, kidney transplantation, quality of life,
• MeSH
• Evropská unie MeSH
• kvalita života MeSH
• lidé MeSH
• průzkumy a dotazníky MeSH
• transplantace ledvin * MeSH
• zaměstnanost MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND This post hoc analysis of data from the prospective OSAKA study evaluated the efficacy and safety of prolonged- and immediate-release tacrolimus in patients who received kidneys from extended-criteria (ECD) and standard-criteria (SCD) donors. MATERIAL AND METHODS Within the ECD and SCD groups, patients were randomized to one of 4 tacrolimus-based regimens (initial dose): Arm 1, immediate-release tacrolimus (0.2 mg/kg/day); Arm 2, prolonged-release tacrolimus (0.2 mg/kg/day); Arm 3, prolonged-release tacrolimus (0.3 mg/kg/day); Arm 4, prolonged-release tacrolimus (0.2 mg/kg/day) plus basiliximab. All patients received mycophenolate mofetil and bolus corticosteroids; Arms 1-3 also received tapered corticosteroids. ECDs met the definition: living/deceased donors aged ≥60 years, or 50-60 years with ≥1 other risk factor, and donation after circulatory death. Primary composite endpoint: graft loss, biopsy-confirmed acute rejection or renal dysfunction by Day 168. Outcomes were compared across treatment arms with the chi-squared or Fisher's exact test. RESULTS A total of 1198 patients were included in the analysis (ECD: n=620 [51.8%], SCD: n=578 [48.2%]). Patients with kidneys from ECDs were older versus SCDs (mean age, 55.7 vs. 44.5 years, p<0.0001). A higher proportion of patients with kidneys from ECDs versus SCDs met the primary composite endpoint (56.8% vs. 32.4%, p<0.0001). However, no statistically significant differences in clinical outcomes or the incidence of treatment-emergent adverse events were seen between treatment arms within each donor group. CONCLUSIONS Worse outcomes were experienced in patients who received kidneys from ECDs versus SCDs. Prolonged-release tacrolimus provided similar graft survival to the immediate-release formulation, with a manageable tolerability profile.

• MeSH
• chronické selhání ledvin chirurgie   MeSH
• dospělí MeSH
• imunosupresiva aplikace a dávkování   MeSH
• imunosupresivní léčba MeSH
• léky s prodlouženým účinkem MeSH
• lidé středního věku MeSH
• lidé MeSH
• přežívání štěpu MeSH
• prospektivní studie MeSH
• rozvrh dávkování léků MeSH
• senioři MeSH
• takrolimus aplikace a dávkování   MeSH
• transplantace ledvin * MeSH
• výběr dárců MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• imunosupresiva MeSH
• léky s prodlouženým účinkem MeSH
• takrolimus MeSH

BACKGROUND: ADVANCE (NCT01304836) was a phase 4, multicenter, prospectively randomized, open-label, 24-week study comparing the incidence of posttransplantation diabetes mellitus (PTDM) with 2 prolonged-release tacrolimus corticosteroid minimization regimens. METHODS: All patients received prolonged-release tacrolimus, basiliximab, mycophenolate mofetil and 1 bolus of intraoperative corticosteroids (0-1000 mg) as per center policy. Patients in arm 1 received tapered corticosteroids, stopped after day 10, whereas patients in arm 2 received no steroids after the intraoperative bolus. The primary efficacy variable was the diagnosis of PTDM as per American Diabetes Association criteria (2010) at any point up to 24 weeks postkidney transplantation. Secondary efficacy variables included incidence of composite efficacy failure (graft loss, biopsy-proven acute rejection or severe graft dysfunction: estimated glomerular filtration rate (Modification of Diet in Renal Disease-4) <30 mL/min per 1.73 m), acute rejection and graft and patient survival. RESULTS: The full-analysis set included 1081 patients (arm 1: n = 528, arm 2: n = 553). Baseline characteristics and mean tacrolimus trough levels were comparable between arms. Week 24 Kaplan-Meier estimates of PTDM were similar for arm 1 versus arm 2 (17.4% vs 16.6%; P = 0.579). Incidence of composite efficacy failure, graft and patient survival, and mean estimated glomerular filtration rate were also comparable between arms. Biopsy-proven acute rejection and acute rejection were significantly higher in arm 2 versus arm 1 (13.6% vs 8.7%, P = 0.006 and 25.9% vs 18.2%, P = 0.001, respectively). Tolerability profiles were comparable between arms. CONCLUSIONS: A prolonged-release tacrolimus, basiliximab, and mycophenolate mofetil immunosuppressive regimen is efficacious, with a low incidence of PTDM and a manageable tolerability profile over 24 weeks of treatment. A lower incidence of biopsy-proven acute rejection was seen in patients receiving corticosteroids tapered over 10 days plus an intraoperative corticosteroid bolus versus those receiving an intraoperative bolus only.

• MeSH
• diabetes mellitus epidemiologie   etiologie   MeSH
• glukokortikoidy aplikace a dávkování   MeSH
• imunosupresiva aplikace a dávkování   MeSH
• imunosupresivní léčba metody   MeSH
• incidence MeSH
• kombinovaná farmakoterapie MeSH
• kyselina mykofenolová aplikace a dávkování   MeSH
• léky s prodlouženým účinkem MeSH
• lidé MeSH
• následné studie MeSH
• prevalence MeSH
• prospektivní studie MeSH
• protinádorová antibiotika aplikace a dávkování   MeSH
• rejekce štěpu prevence a kontrola   MeSH
• takrolimus aplikace a dávkování   MeSH
• transplantace ledvin škodlivé účinky   MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze IV MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH
• Názvy látek
• glukokortikoidy MeSH
• imunosupresiva MeSH
• kyselina mykofenolová MeSH
• léky s prodlouženým účinkem MeSH
• protinádorová antibiotika MeSH
• takrolimus MeSH

BACKGROUND: The once-daily (QD), prolonged-release formulation of tacrolimus has been shown to improve adherence versus twice-daily (BD) tacrolimus. Treatment nonadherence in transplant recipients has been associated with poor graft outcomes. METHODS: This open-label, parallel-group study randomized adults with end-stage renal disease undergoing primary kidney transplantation or retransplantation to an initial dose of tacrolimus BD 0.2 mg/kg per day (Arm 1; n=309), QD 0.2 mg/kg per day (Arm 2; n=302), QD 0.3 mg/kg per day (Arm 3; n=304) all with mycophenolate mofetil and corticosteroids (tapered) over 24 weeks, or tacrolimus QD 0.2 mg/kg per day with mycophenolate mofetil, basiliximab, and corticosteroids given only perioperatively (Arm 4; n=283). The primary composite endpoint (efficacy failure; per protocol set) was defined as graft loss, biopsy-confirmed acute rejection, or graft dysfunction at week 24. Graft dysfunction was defined as estimated glomerular filtration rate Modification of Diet in Renal Disease-4 formula of less than 40 mL/min/1.73 m(2). The prespecified noninferiority margin was 12.5%. RESULTS: The per protocol set included 976 patients: 237, 263, 246, and 230 patients in Arms 1 to 4, respectively. Noninferiority of the composite endpoint was demonstrated for Arm 2 versus Arm 1; Kaplan-Meier estimates of efficacy failure were 42.2% and 40.6%, respectively (difference, -1.6%; 95% confidence interval [CI], -12.2% to 9.0%). Noninferiority to Arm 1 was not confirmed for Arm 3 (difference, -3.5%; 95% CI, -13.6% to 6.6%) or Arm 4 (difference, -7.1%; 95% CI, -16.1% to 1.9%). Graft dysfunction (estimated glomerular filtration rate <40 mL/min/1.73 m(2)) was the main determinant of composite-endpoint efficacy failure across all arms. CONCLUSIONS: In patients representative of the European kidney transplant population, tacrolimus QD-based immunosuppression (0.2 mg/kg/day), without induction, showed similar efficacy to 0.2 mg/kg per day tacrolimus BD.

• MeSH
• biopsie MeSH
• chronické selhání ledvin chirurgie   MeSH
• dospělí MeSH
• imunosupresiva aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• rejekce štěpu diagnóza   farmakoterapie   MeSH
• rozvrh dávkování léků MeSH
• takrolimus aplikace a dávkování   MeSH
• transplantace ledvin * MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• imunosupresiva MeSH
• takrolimus MeSH